Remarkably similar CTLA-4 binding properties of therapeutic ipilimumab and tremelimumab antibodies.

Mengnan He,Shuguang Tan,Jinghua Yan,Jianxun Qi,Catherine W.H Zhang,Yi Shi,Yan Chai,George F Gao,Zhou Tong

doi:10.18632/oncotarget.18004

Abstract

Monoclonal antibody based immune checkpoint blockade therapies have achieved clinical successes in management of malignant tumors. As the first monoclonal antibody targeting immune checkpoint molecules entered into clinics, the molecular basis of ipilimumab-based anti-CTLA-4 blockade has not yet been fully understood. In the present study, we report the complex structure of ipilimumab and CTLA-4. The complex structure showed similar contributions from VH and VL of ipilimumab in binding to CTLA-4 front β-sheet strands. The blockade mechanism of ipilimumab is that the strands of CTLA-4 contributing to the binding to B7-1 or B7-2 were occupied by ipilimumab and thereafter prevents the binding of B7-1 or B7-2 to CTLA-4. Though ipilimumab binds to the same epitope with tremelimumab on CTLA-4 with similar binding affinity, the higher dissociation rate of ipilimumab may indicate the dynamic binding to CTLA-4, which may affect its pharmacokinetics. The molecular basis of ipilimumab-based anti-CTLA-4 blockade and comparative study of the binding characteristics of ipilimumab and tremelimumab would shed light for the discovery of small molecular inhibitors and structure-based monoclonal antibody optimization or new biologics.

Highlights

The approval of anti-CTLA-4 monoclonal antibody (MAb), ipilimumab (MDX-010, Yervoy) from BristolMyers Squibb (New York, US), by US Food and Drug Administration (FDA) in 2011 has initiated a new era for tumor immunotherapy
The blockade mechanism of ipilimumab is that the strands of CTLA-4 contributing to the binding to B7-1 or B7-2 were occupied by ipilimumab and thereafter prevents the binding of B7-1 or B7-2 to CTLA-4
We reported the structural basis of the first clinically applied anti-CTLA-4 MAb, the ipilimumab

Summary

Introduction

The approval of anti-CTLA-4 monoclonal antibody (MAb), ipilimumab (MDX-010, Yervoy) from BristolMyers Squibb (New York, US), by US Food and Drug Administration (FDA) in 2011 has initiated a new era for tumor immunotherapy. The “two signal” model of naïve T cell activation involves the recognition of T cell receptor (TCR) and peptide major histocompatibility complex (pMHC) as the first signal, and the interaction between co-stimulators and their ligands, such as CD28 and B7-1, as the second signal [1,2,3,4]. CTLA-4 is a member of CD28-B7 immunoglobulin superfamily of immune regulatory molecules which acts as a negative regulator of T cell activation, especially CD28-dependent T cell responses [5]. CTLA-4 functions to inhibit T cell activity via the binding to common ligands with CD28, the B7-1 (CD80) or B7-2 (CD86), with significantly higher binding affinity than that with CD28 [9]. The complex structures of CTLA-4 and www.impactjournals.com/oncotarget

Methods

Results

Conclusion